Journal Article

Exogenous and endogenous ceramides elicit volume-sensitive chloride current in ventricular myocytes

Frank J. Raucci, Dayanjan S. Wijesinghe, Charles E. Chalfant and Clive M. Baumgarten

in Cardiovascular Research

Published on behalf of European Society of Cardiology

Volume 86, issue 1, pages 55-62
Published in print April 2010 | ISSN: 0008-6363
Published online December 2009 | e-ISSN: 1755-3245 | DOI: https://dx.doi.org/10.1093/cvr/cvp399
Exogenous and endogenous ceramides elicit volume-sensitive chloride current in ventricular myocytes

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Aims

Because ceramide accumulates in several forms of cardiovascular disease and ceramide-induced apoptosis may involve the volume-sensitive Cl current, ICl,swell, we assessed whether ceramide activates ICl,swell.

Methods and results

ICl,swell was measured in rabbit ventricular myocytes by whole-cell patch clamp after isolating anion currents. Exogenous C2-ceramide (C2-Cer), a membrane-permeant short-chain ceramide, elicited an outwardly rectifying Cl current in both physiological and symmetrical Cl solutions that was fully inhibited by DCPIB, a specific ICl,swell blocker. In contrast, the metabolically inactive C2-Cer analogue C2-dihydroceramide (C2-H2Cer) failed to activate Cl current. Bacterial sphingomyelinase (SMase), which generates endogenous long-chain ceramides as was confirmed by tandem mass spectrometry, also elicited an outwardly rectifying Cl current that was inhibited by DCPIB and tamoxifen, another ICl,swell blocker. Bacterial SMase-induced current was partially reversed by osmotic shrinkage and fully suppressed by ebselen, a scavenger of reactive oxygen species. Outward rectification with physiological and symmetrical Cl gradients, block by DCPIB and tamoxifen, and volume sensitivity are characteristics that identify ICl,swell. Insensitivity to C2-H2Cer and block by ebselen suggest involvement of ceramide signalling rather than direct lipid-channel interaction.

Conclusion

Exogenous and endogenous ceramide elicited ICl,swell in ventricular myocytes. This may contribute to persistent activation of ICl,swell and aspects of altered myocyte function in cardiovascular diseases associated with by ceramide accumulation.

Keywords: Cl channel; Ceramide; Sphingomyelinase; ICl,swell; VRAC

Journal Article.  4516 words.  Illustrated.

Subjects: Cardiovascular Medicine

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